Tag Archives: vasoactive drugs

A study comparing mean arterial pressure (MAP) targets of 80 to 85 mm Hg (high-target group) with 65 to 70 mm Hg (low-target group) n 776 septic shock patients – the SEPSISPAM study – did not show a difference in the primary endpoint of 28 day mortality. Among patients with chronic hypertension, those in the high-target group required less renal-replacement therapy than did those in the low-target group. In my view this supports an approach that targets MAP based on the individual patient’s history rather than a blanket one-number-fits-all approach. The MAPs actually achieved in the low-target group were between 70-75 mm of Hg.

Background: The Surviving Sepsis Campaign recommends targeting a mean arterial pressure of at least 65 mm Hg during initial resuscitation of patients with septic shock. However, whether this blood-pressure target is more or less effective than a higher target is unknown.

Methods: In 31 emergency departments in the United States, we randomly assigned patients with septic shock to one of three groups for 6 hours of resuscitation: protocol-based EGDT; protocol-based standard therapy that did not require the placement of a central venous catheter, administration of inotropes, or blood transfusions; or usual care. The primary end point was 60-day in-hospital mortality. We tested sequentially whether protocol-based care (EGDT and standard-therapy groups combined) was superior to usual care and whether protocol-based EGDT was superior to protocol-based standard therapy. Secondary outcomes included longer-term mortality and the need for organ support.

Results: At 28 days, there was no significant between-group difference in mortality, with deaths reported in 142 of 388 patients in the high-target group (36.6%) and 132 of 388 patients in the low-target group (34.0%) (hazard ratio in the high-target group, 1.07; 95% confidence interval [CI], 0.84 to 1.38; P=0.57). There was also no significant difference in mortality at 90 days, with 170 deaths (43.8%) and 164 deaths (42.3%), respectively (hazard ratio, 1.04; 95% CI, 0.83 to 1.30; P=0.74). The occurrence of serious adverse events did not differ significantly between the two groups (74 events [19.1%] and 69 events [17.8%], respectively; P=0.64). However, the incidence of newly diagnosed atrial fibrillation was higher in the high-target group than in the low-target group. Among patients with chronic hypertension, those in the high-target group required less renal-replacement therapy than did those in the low-target group, but such therapy was not associated with a difference in mortality.

Conclusions: Targeting a mean arterial pressure of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg, in patients with septic shock undergoing resuscitation did not result in significant differences in mortality at either 28 or 90 days.

The first of three major trials assessing early goal directed therapy (EGDT) in sepsis – the American ProCESS Trial – has been published.

It showed what many of us thought – that the specific monitoring via a central line of central venous oxygen saturation – was not necessary for improved survival.

However the trial randomised 1341 patients to one of three arms:
(1) protocolised EGDT
(2) protocol-based standard therapy that did not require the placement of a central venous catheter, administration of inotropes, or blood transfusions
(3) ‘usual care’ which was not standardised.

There were no differences in any of the primary or secondary outcomes between the groups.

Interestingly, in the six hours of early care that the trial dictated, the volume of intravenous fluids administered differed significantly among the groups (2.8 litres in the protocol-based EGDT group, 3.3 litres in the protocol-based standard-therapy group, and 2.3 litres in the usual-care group).

There was also a difference in the amount of vasopressor given, with more patients in the two protocol-based groups receiving vasopressors (54.9% in the protocol-based EGDT group, 52.2% in the protocol-based standard-therapy group, 44.1% in the usual-care group).

The use of intravenous fluids, vasopressors, dobutamine, and blood transfusions between 6 and 72 hours did not differ significantly among the groups.

Overall 60 day mortality was in the region of 20% for all groups.

What are the take home points here? Firstly, overall sepsis outcomes have improved over recent years, and early recognition and antibiotic administration may be the most important components of care. In the early emergency department phase of care, protocolised fluid and vasopressor therapy may not be as important as we thought. Good clinical assessment and regular review seem to be as effective and perhaps more important than any specific monitoring modality or oxygen delivery-targeted drug and blood therapy.

We all await the ARISE and ProMISE studies which may shed more light on the most important components of early sepsis care.

Background: In a single-center study published more than a decade ago involving patients presenting to the emergency department with severe sepsis and septic shock, mortality was markedly lower among those who were treated according to a 6-hour protocol of early goal-directed therapy (EGDT), in which intravenous fluids, vasopressors, inotropes, and blood transfusions were adjusted to reach central hemodynamic targets, than among those receiving usual care. We conducted a trial to determine whether these findings were generalizable and whether all aspects of the protocol were necessary.

Methods: In 31 emergency departments in the United States, we randomly assigned patients with septic shock to one of three groups for 6 hours of resuscitation: protocol-based EGDT; protocol-based standard therapy that did not require the placement of a central venous catheter, administration of inotropes, or blood transfusions; or usual care. The primary end point was 60-day in-hospital mortality. We tested sequentially whether protocol-based care (EGDT and standard-therapy groups combined) was superior to usual care and whether protocol-based EGDT was superior to protocol-based standard therapy. Secondary outcomes included longer-term mortality and the need for organ support.

Results: We enrolled 1341 patients, of whom 439 were randomly assigned to protocol-based EGDT, 446 to protocol-based standard therapy, and 456 to usual care. Resuscitation strategies differed significantly with respect to the monitoring of central venous pressure and oxygen and the use of intravenous fluids, vasopressors, inotropes, and blood transfusions. By 60 days, there were 92 deaths in the protocol-based EGDT group (21.0%), 81 in the protocol-based standard-therapy group (18.2%), and 86 in the usual-care group (18.9%) (relative risk with protocol-based therapy vs. usual care, 1.04; 95% confidence interval [CI], 0.82 to 1.31; P=0.83; relative risk with protocol-based EGDT vs. protocol-based standard therapy, 1.15; 95% CI, 0.88 to 1.51; P=0.31). There were no significant differences in 90-day mortality, 1-year mortality, or the need for organ support.

Conclusions: In a multicenter trial conducted in the tertiary care setting, protocol-based resuscitation of patients in whom septic shock was diagnosed in the emergency department did not improve outcomes

There’s so much debate on which components of Early Goal Directed Therapy in sepsis really make a difference. The good news is that three randomised controlled trials in the UK, Australasia, and North America, aim to answer the question, and the study design from the outset has been a collaboration that will allow the results to be pooled.

Counterintuitive as it sounds, this is pretty cool. I blogged about these guys before when they published their findings on microcirculatory flow in septic patients given beta blockers.

It’s a small study – 77 patients with septic shock and a heart rate of 95/min or higher requiring high-dose norepinephrine to maintain a mean arterial pressure of at least 65 mm Hg were randomised to receive a continuous infusion of esmolol titrated to maintain heart rate between 80/min and 94/min for their ICU stay. 77 patients received standard treatment. It should be noted the primary outcome (target heart rate) was not a patient-oriented endpoint. Interestingly though, there were no increased adverse events in the beta blocker group, which demonstrated improved left ventricular stroke work, lower lactate levels, decreased noradrenaline and fluid requirements, improved oxygenation, and a lower mortality.

Caution is appropriate here though: this study was a small, single-centre open-label trial. It will be very interesting to see if these effects are reproduced and whether they will ultimately translate to meaningful outcome benefits.

IMPORTANCE: β-Blocker therapy may control heart rate and attenuate the deleterious effects of β-adrenergic receptor stimulation in septic shock. However, β-Blockers are not traditionally used for this condition and may worsen cardiovascular decompensation related through negative inotropic and hypotensive effects.

OBJECTIVE: To investigate the effect of the short-acting β-blocker esmolol in patients with severe septic shock.

DESIGN, SETTING, AND PATIENTS: Open-label, randomized phase 2 study, conducted in a university hospital intensive care unit (ICU) between November 2010 and July 2012, involving patients in septic shock with a heart rate of 95/min or higher requiring high-dose norepinephrine to maintain a mean arterial pressure of 65 mm Hg or higher.

INTERVENTIONS: We randomly assigned 77 patients to receive a continuous infusion of esmolol titrated to maintain heart rate between 80/min and 94/min for their ICU stay and 77 patients to standard treatment.

MAIN OUTCOMES AND MEASURES: Our primary outcome was a reduction in heart rate below the predefined threshold of 95/min and to maintain heart rate between 80/min and 94/min by esmolol treatment over a 96-hour period. Secondary outcomes included hemodynamic and organ function measures; norepinephrine dosages at 24, 48, 72, and 96 hours; and adverse events and mortality occurring within 28 days after randomization.

RESULTS: Targeted heart rates were achieved in all patients in the esmolol group compared with those in the control group. The median AUC for heart rate during the first 96 hours was -28/min (IQR, -37 to -21) for the esmolol group vs -6/min (95% CI, -14 to 0) for the control group with a mean reduction of 18/min (P < .001). For stroke volume index, the median AUC for esmolol was 4 mL/m2 (IQR, -1 to 10) vs 1 mL/m2 for the control group (IQR, -3 to 5; P = .02), whereas the left ventricular stroke work index for esmolol was 3 mL/m2 (IQR, 0 to 8) vs 1 mL/m2 for the control group (IQR, -2 to 5; P = .03). For arterial lactatemia, median AUC for esmolol was -0.1 mmol/L (IQR, -0.6 to 0.2) vs 0.1 mmol/L for the control group (IQR, -0.3 for 0.6; P = .007); for norepinephrine, -0.11 μg/kg/min (IQR, -0.46 to 0.02) for the esmolol group vs -0.01 μg/kg/min (IQR, -0.2 to 0.44) for the control group (P = .003). Fluid requirements were reduced in the esmolol group: median AUC was 3975 mL/24 h (IQR, 3663 to 4200) vs 4425 mL/24 h(IQR, 4038 to 4775) for the control group (P

CONCLUSIONS AND RELEVANCE: For patients in septic shock, open-label use of esmolol vs standard care was associated with reductions in heart rates to achieve target levels, without increased adverse events. The observed improvement in mortality and other secondary clinical outcomes warrants further investigation.

They included patients who had been fluid resuscitated and who required noradrenaline, and treated them with a titrated esmolol infusion commenced at 25 mg/hr, with an upper dose limit of 2,000 mg/hr, to maintain a predefined HR range between 80 and 94 beats per minute. Esmolol was chosen because of its half-life of approximately 2 min, so any adverse effects could be rapidly reversed. They examined the macrocirculation using pulmonary artery catheterisation and the microcirculation using sublingual microvascular blood flow imaging.

Most of the patients had pneumonia, and interestingly, all patients received intravenous hydrocortisone (200mg/d) as a continuous infusion.

In this small cohort of patients, they found that titrating the heart rate to less than 95 bpm was associated with maintenance of stroke volume and preservation of microvascular blood flow. Although cardiac output fell because of the lower HR, stroke volume, MAP, and lactate levels were unchanged while noradrenaline requirements were reduced.

Increased vascular reactivity to norepinephrine following nonselective β-blockade is supported by volunteer and animal studies, and postulated mechanisms include:

blockade of a peripheral β2-mediated vasodilatory effect of noradrenaline

OBJECTIVE: β-blocker therapy may control heart rate and attenuate the deleterious effects of β-stimulating catecholamines in septic shock. However, their negative chronotropy and inotropy may potentially lead to an inappropriately low cardiac output, with a subsequent compromise of microvascular blood flow. The purpose of the present pilot study was to investigate the effects of reducing heart rate to less than 95 beats per minute in patients with septic shock using the β-1 adrenoceptor blocker, esmolol, with specific focus on systemic hemodynamics and the microcirculation.

CONCLUSIONS: This pilot study demonstrated that heart rate control by a titrated esmolol infusion in septic shock patients was associated with maintenance of stroke volume, preserved microvascular blood flow, and a reduction in norepinephrine requirements.

Interesting new drug to know about: Serelaxin, recombinant human relaxin-2. It’s hard to assess the clinical significance of the statistically significant findings. Let’s see if a benefit is replicated in future studies. It’s hard to imagine a normotensive patient that can’t be fixed with existing therapies though.

BACKGROUND: Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic effects. In a pilot study, serelaxin was safe and well tolerated with positive clinical outcome signals in patients with acute heart failure. The RELAX-AHF trial tested the hypothesis that serelaxin-treated patients would have greater dyspnoea relief compared with patients treated with standard care and placebo.

METHODS: RELAX-AHF was an international, double-blind, placebo-controlled trial, enrolling patients admitted to hospital for acute heart failure who were randomly assigned (1:1) via a central randomisation scheme blocked by study centre to standard care plus 48-h intravenous infusions of placebo or serelaxin (30 μg/kg per day) within 16 h from presentation. All patients had dyspnoea, congestion on chest radiograph, increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic blood pressure greater than 125 mm Hg. Patients, personnel administering study drug, and those undertaking study-related assessments were masked to treatment assignment. The primary endpoints evaluating dyspnoea improvement were change from baseline in the visual analogue scale area under the curve (VAS AUC) to day 5 and the proportion of patients with moderate or marked dyspnoea improvement measured by Likert scale during the first 24 h, both analysed by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00520806.

INTERPRETATION: Treatment of acute heart failure with serelaxin was associated with dyspnoea relief and improvement in other clinical outcomes, but had no effect on readmission to hospital. Serelaxin treatment was well tolerated and safe, supported by the reduced 180-day mortality

A subset of patients from the 2008 Vasopressin and Septic Shock Trial (VASST) trial had invasive haemodynamic monitoring measurements from pulmonary artery catheters. These data have now been analysed, revealing that vasopressin was associated with a lower heart rate compared with norepinephrine (noradrenaline) alone, without significant difference in cardiac index or stroke volume index. However, there was significantly greater use of inotropic drugs in the vasopressin group compared with the norepinephrine group.

Tachycardia and high quantities of catecholamine infusion are both associated with mortality in sepsis. The authors discuss:

“The idea of decatecholaminization, reducing both endogenous and exogenous adrenergic stimulation, is now believed to be an important treatment strategy, and the use of beta-blockers in septic shock is being considered. The early use of vasopressin or speciﬁc V1a receptor agonists in early septic shock may be another possible treatment.”

This interesting post-hoc analysis may help further define the patients in whom vasopressin is to be considered, by those clinicians who are using it in septic shock. For those that aren’t, I wouldn’t worry about it.

BACKGROUND: Vasopressin is known to be an effective vasopressor in the treatment of septic shock, but uncertainty remains about its effect on other hemodynamic parameters.

METHODS: We examined the cardiopulmonary effects of vasopressin compared with norepinephrine in 779 adult patients with septic shock recruited to the Vasopressin and Septic Shock Trial. More detailed cardiac output data were analyzed for a subset of 241 patients managed with a pulmonary artery catheter, and data were collected for the first 96 h after randomization. We compared the effects of vasopressin vs norepinephrine in all patients and according to severity of shock (< 15 or ≥ 15 μg/min of norepinephrine) and cardiac output at baseline.

RESULTS: Equal BPs were maintained in both treatment groups, with a significant reduction in norepinephrine requirements in the patients treated with vasopressin. The major hemodynamic difference between the two groups was a significant reduction in heart rate in the patients treated with vasopressin (P < .0001), and this was most pronounced in the less severe shock stratum (treatment × shock stratum interaction, P =.03). There were no other major cardiopulmonary differences between treatment groups, including no difference in cardiac index or stroke volume index between patients treated with vasopressin and those treated with norepinephrine. There was significantly greater use of inotropic drugs in the vasopressin group than in the norepinephrine group.

CONCLUSIONS: Vasopressin treatment in septic shock is associated with a significant reduction in heart rate but no change in cardiac output or other measures of perfusion.

Despite intravenous nitrate boluses being used in original studies demonstrating benefit in acute heart failure1,2, I regularly meet reluctance from both physicians and nurses in the emergency department to give them.

Their resistance seems to be based on a concern for inducing hypotension, and they prefer to ‘titrate up’ an infusion.

There are a number of reasons to avoid starting with a low rate infusion in a sick heart failure patient.

Matthew Reed highlighted cannula size as an important factor4:

If a GTN infusion is commenced at a rate of 1 ml/h, a critically unwell patient with a large cannula—for example, a grey cannula (16G) — will have to wait over 6 min for the drug to enter the body. This compares with 1.5 min for a pink cannula (20G) at the same infusion rate. If a large-diameter cannula is chosen for these patients, then a fast initial infusion rate should also be chosen to ensure that the GTN begins to act quickly.

(1) mechanical slack within an infusion device may mean an infusion set at 1 ml/h will take many minutes for the driver to contact and advance the syringe plunger. For this reason, infusions should be purged before patient connection.

(2) the pharmacokinetics of the drug should be considered. At low infusion rates it will take significant time for a steady state to be achieved (a drug such as GTN, with a half-life of 2 min, would require 10 min to achieve steady state). For clinical effects to be seen quickly, a bolus should be given before commencing infusions.

(3) the use of 1 ml/h infusions (8 µg/min using a 0.5% solution) may be excessively cautious – the British National Formulary recommends a therapeutic dose range from 10 to 200 µg/min. Furthermore, there is emerging evidence that, when used for decompensated heart failure, higher doses of GTN are associated with more favourable outcomes.

(4) at low infusion rates any obstruction in the intravenous system will take a proportionally longer time to become apparent, as it will take longer for the pressure to build up and trigger the syringe pump’s high pressure alarm..

Now a recent study confirms such a regimen can be used safely in the elderly. ISDN 3mg bolus treatment was not associated with higher rates of hypotension in the elderly population treated for heart failure in the emergency department. Despite a small study and a retrospective design, this lends support to the practice of iv bolus nitrate therapy for acute heart failure, even in the elderly.

A single case report might not be practice changing, but it’s helpful to know about this option:

A patient with acute intracerebral haemorrhage developed hyoxaemia due to neurogenic pulmonary oedema, accompanied by a labile blood pressure and elevated catecholamine levels.

Nicardipine and other antihypertensive agents including metoprolol, hydralazine, and labetalol were tried without benefit, and the patient continued to deteriorate.

Phentolamine was tried. The introduction, withdrawal, and reintroduction of phentolamine and the clinical status of the patient is described convincingly:

a phentolamine infusion was started at 0.17 mg/min and titrated for BP control. Over 6 h, the FIO2 requirements dropped precipitously, gas exchange improved, and the chest radiograph showed improvement of pulmonary edema. When the hospital supply of phentolamine was exhausted, the clinical status deteriorated rapidly. Within just 15 h of the discontinuation of phentolamine, the PaO2 fell from 166 mm Hg to 66 mm Hg, and FIO2 requirements rose from 60% to 100%. When the phentolamine supply was replenished and the infusion restarted, the same rapid improvement was observed and BP stabilized.

Abstract
Neurogenic pulmonary edema (NPE) is a clinical syndrome characterized by the acute onset of pulmonary edema following a significant CNS insult. The cause is believed to be a surge of catecholamines that results in cardiopulmonary dysfunction. Although there are myriad case reports describing CNS events that are associated with this syndrome, few studies have identified specific treatment modalities. We present a case of NPE caused by an intracranial hemorrhage from a ruptured arteriovenous malformation. We uniquely document a rise and fall of serum catecholamine levels correlating with disease activity and a dramatic clinical response to IV phentolamine.

A systematic review and meta-analysis of randomised controlled trials showed dobutamine is not associated with improved mortality in heart failure patients and in the case of severe heart failure there is some suggestion of increased mortality, although this did not reach statistical significance.

The authors do point out that the quality of the reports of the trials reviewed was suboptimal. However, they state:
It should be noted that the results of this study are in accord with large observational studies that have also suggested harm associated with use of dobutamine in patients with severe heart failure. Taken together, this evidence should cause clinicians to reconsider their use of dobutamine in patients with heart failure, particularly those most at risk of the adverse effects, those with underlying ischaemic heart disease.

PURPOSE: Dobutamine is recommended for patients with severe heart failure; however uncertainty exists as to its effect on mortality. This study aims to critically review the literature to evaluate whether dobutamine, compared with placebo or standard care, is associated with lower mortality and a range of secondary outcomes, in patients with severe heart failure.

METHODS: A systematic review and meta-analysis of randomised controlled trials was performed. PubMed, EMBASE, the Cochrane Central Trials Registry, the metaRegister of Controlled Trials and bibliographies of retrieved articles were searched. Randomised trials comparing dobutamine with placebo or standard care, in human, adult patients with severe heart failure, were included if they reported at least one outcome of interest. Data regarding trial validity, methodological processes and clinical outcomes were extracted, and a meta-analysis was performed.

CONCLUSIONS: This meta-analysis showed that dobutamine is not associated with improved mortality in patients with heart failure, and there is a suggestion of increased mortality associated with its use, although this did not reach the conventional level of statistical significance. Further research to define the role of dobutamine in treatment of severe heart failure should be a priority.